TW201305166A - Process for the preparation of chiral 8-(3-aminopiperidin-1-yl)-xanthines - Google Patents

Process for the preparation of chiral 8-(3-aminopiperidin-1-yl)-xanthines Download PDF

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TW201305166A
TW201305166A TW101117498A TW101117498A TW201305166A TW 201305166 A TW201305166 A TW 201305166A TW 101117498 A TW101117498 A TW 101117498A TW 101117498 A TW101117498 A TW 101117498A TW 201305166 A TW201305166 A TW 201305166A
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methyl
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butyn
phenyl
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Waldemar Pfrengle
Thorsten Pachur
Thomas Nicola
Adil Duran
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Boehringer Ingelheim Int
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Abstract

The invention relates to an improved method for producing enantiomer-free 8- (3-amino-piperidin-1-yI)-xanthines.

Description

對掌性8-(3-胺基六氫吡啶-1-基)-黃嘌呤之製法 Preparation method of palmitic 8-(3-aminohexahydropyridin-1-yl)-xanthine

本發明係關於製備對掌性8-(3-胺基六氫吡啶-1-基)-黄嘌呤、其對掌異構物及其生理上可耐受鹽類之改良方法。 This invention relates to an improved process for the preparation of palmitic 8-(3-aminohexahydropyridin-1-yl)-xanthine, its palmar isomers and physiologically tolerable salts thereof.

下列一般結構之8-(3-胺基六氫吡啶-1-基)-黄嘌呤 其中R1為，例如一視需要經取代之芳基甲基或一視需要經取代之雜芳基甲基，R2為，例如一烷基，及R3為，例如一視需要經取代之苯甲基或一直鏈或支鏈烯基或炔基，已從國際專利申請案WO 02/068420、WO 04/018468、WO 04/018467、WO 2004/041820及WO 2004/046148中得知，其中描述了具有珍貴藥理性質之化合物，其包括，特別是對酵素二肽醯肽酶IV(DPP-IV)活性之抑制作用。因此，此類化合物適合用於預防或治療與增加的DPP-IV活性有關聯之疾病或症狀，或其可藉由降低DPP-IV活性來預防或減輕疾病或症狀，特別是第I型或第II型糖尿病或低葡萄糖耐受。 The following general structure of 8-(3-aminohexahydropyridin-1-yl)-xanthine Wherein R 1 is, for example, an optionally substituted arylmethyl group or a heteroarylmethyl group which is optionally substituted, R 2 is, for example, an alkyl group, and R 3 is, for example, optionally substituted. A benzyl or a straight or branched alkenyl or alkynyl group is known from the international patent applications WO 02/068420, WO 04/018468, WO 04/018467, WO 2004/041820 and WO 2004/046148, wherein Compounds having valuable pharmacological properties are described which include, inter alia, inhibition of the activity of the enzyme dipeptide prion peptidase IV (DPP-IV). Accordingly, such compounds are suitable for use in preventing or treating a disease or condition associated with increased DPP-IV activity, or they may prevent or alleviate a disease or condition by reducing DPP-IV activity, particularly Type I or Type II diabetes or low glucose tolerance.

WO 04/018468揭示了一種製備方法，其中8-(3-胺基六氫吡啶-1-基)-黄嘌呤係藉由將對應的通式(II)之第三-丁氧基羰基-保護衍生物去保護來製備。 WO 04/018468 discloses a preparation process in which 8-(3-aminohexahydropyridin-1-yl)-xanthine is protected by a corresponding third-butoxycarbonyl group of the formula (II) The derivative is deprotected to prepare.

在此方法中，雜質很難移除，特別是在工業級製造上會發生，且可歸因於所用的保護基。因此，此方法不適合用於工業上製備8-(3-胺基六氫吡啶-1-基)-黄嘌呤，特別是對純度有嚴格要求之藥品製造業。再者，此方法具有在製造對掌異構性純前驅物3-(第三-丁氧基羰基胺基)六氫吡啶上複雜且昂貴之缺點。然而，由於副作用的風險及將劑量降至最低的考量，對掌異構純活性物質對醫藥的應用係較佳的。這些情況對該現知之工業製備對掌異構性純8-(3-胺基六氫吡啶-1-基)-黄嘌呤之適用性為不利的。. In this process, impurities are difficult to remove, especially in industrial grade manufacturing, and can be attributed to the protecting groups used. Therefore, this method is not suitable for the industrial preparation of 8-(3-aminohexahydropyridin-1-yl)-xanthine, especially for the pharmaceutical manufacturing industry which has strict requirements on purity. Moreover, this method has the disadvantage of being complicated and expensive in the manufacture of 3-(tris-butoxycarbonylamino)hexahydropyridine, a pure precursor of the palmier isomer. However, due to the risk of side effects and the minimization of dosage, the application of the palmitic isotope active substance to medicine is preferred. These conditions are detrimental to the applicability of the known industrial preparation to palmitic isomerization of pure 8-(3-aminohexahydropyridin-1-yl)-xanthine. .

考慮了上述該現知製備方法之缺點，本發明之目的係提供一種使用現成的高化學及光學純度之起始物質，及無高技術成本及不便性下製備對掌異構性純8-(3-胺基六氫吡啶-1-基)-黄嘌呤之方法。該新穎方法亦適用於工業級合成，因此可作為商業應用。 In view of the above disadvantages of the prior art preparation method, the object of the present invention is to provide a starting material which is ready for use in high chemical and optical purity, and which is free of high technical cost and inconvenience to prepare pure palmar isomers 8-(( A method of 3-aminopyridin-1-yl)-xanthine. This novel method is also suitable for industrial grade synthesis and is therefore commercially available.

此目的可藉由以本發明之方法製備對掌性8-(3-胺基六氫吡啶-1-基)-黄嘌呤來達成。除了高產率的工業表現外，絕佳的化學及光學純度為本發明合成路徑之其他的優點。 This object can be achieved by preparing palmitic 8-(3-aminohexahydropyridin-1-yl)-xanthine by the method of the present invention. In addition to high yield industrial performance, excellent chemical and optical purity are other advantages of the synthetic route of the present invention.

根據本發明之方法，適當的黄嘌呤前驅物(III)係根據流 程1與對掌異構性純的或外消旋之(3-酞醯胺基)-六氫吡啶，在適當的溶劑中於20至160℃、較佳為8至140℃的溫度下反應；所用的溶劑，例如可為四氫呋喃(THF)、二烷、N,N-二甲基甲醯胺(DMF)、二甲基乙醯胺(DMA)、N-甲基-2-吡咯酮(NMP)或二甲基亞碸(DMSO)。較佳的係使用NMP。隨後以本身已知之方法將酞基分開。可能的分開方法係描述於，例如T.W.Greene之"Protective Groups in Organic Synthesis",Wiley 1981，第265頁(例如溶於乙醇中之肼)。 According to the process of the present invention, the appropriate xanthine precursor (III) is in accordance with Scheme 1 and the palmitic isomerization of pure or racemic (3-amidino)-hexahydropyridine in a suitable solvent. The reaction is carried out at a temperature of 20 to 160 ° C, preferably 8 to 140 ° C; the solvent used may be, for example, tetrahydrofuran (THF), Alkane, N,N-dimethylformamide (DMF), dimethylacetamide (DMA), N-methyl-2-pyrrolidone (NMP) or dimethylammonium (DMSO). Preferably, NMP is used. The sulfhydryl groups are then separated in a manner known per se. Possible separation methods are described, for example, in "Protective Groups in Organic Synthesis" by TW Greene, Wiley 1981, page 265 (e.g., in ethanol).

在上述的化學式中，X為離去基，其係選自鹵素之基團，例如氟、氯或溴原子，或磺醯酯之基團，例如苯基磺醯基氧基、對甲苯磺醯基氧基、甲基磺醯基氧基或三氟甲基磺醯基氧基。 In the above formula, X is a leaving group selected from a halogen group such as a fluorine, chlorine or bromine atom, or a sulfonate group such as phenylsulfonyloxy or p-toluenesulfonate. Alkoxy, methylsulfonyloxy or trifluoromethylsulfonyloxy.

R1為苯基羰基甲基、苯甲基、萘基甲基、吡啶基甲基、嘧啶基甲基、喹啉基甲基，異喹啉基甲基、喹唑啉基甲基、喹啉基甲基、萘啶基甲基或啡啶基甲基，其中芳 香或雜芳香基團在各情況下係經Ra單或雙取代，而其取代基可為相同或不同，及Ra為氫、氟、氯或溴原子或氰基、甲基、三氟甲基、乙基、苯基、甲氧基、二氟甲氧基、三氟甲氧基或乙氧基，或二個Ra基，當與相鄰的碳原子鍵結時，亦可為-O-CH2-O-或-O-CH2-CH2-O-基，R2為甲基、乙基、丙基、異丙基、環丙基或苯基及R3為2-丁烯-1-基、3-甲基-2-丁烯-1-基、2-丁炔-1-基、2-氟苯甲基、2-氯苯甲基、2-溴苯甲基、2-碘苯甲基、2-甲基苯甲基、2-(三氟甲基)苯甲基或2-氰基苯甲基。 R 1 is phenylcarbonylmethyl, benzyl, naphthylmethyl, pyridylmethyl, pyrimidinylmethyl, quinolylmethyl, isoquinolinylmethyl, quinazolinylmethyl, quinolin a morphylmethyl, naphthyridylmethyl or morphipylmethyl group, wherein the aromatic or heteroaromatic group is in each case mono- or disubstituted by R a , and the substituents may be the same or different, and R a Is a hydrogen, fluorine, chlorine or bromine atom or cyano, methyl, trifluoromethyl, ethyl, phenyl, methoxy, difluoromethoxy, trifluoromethoxy or ethoxy, or two The R a group, when bonded to an adjacent carbon atom, may also be -O-CH 2 -O- or -O-CH 2 -CH 2 -O- group, and R 2 is a methyl group, an ethyl group, or a C group. Base, isopropyl, cyclopropyl or phenyl and R 3 are 2-buten-1-yl, 3-methyl-2-buten-1-yl, 2-butyn-1-yl, 2- Fluorobenzyl, 2-chlorobenzyl, 2-bromobenzyl, 2-iodobenzyl, 2-methylbenzyl, 2-(trifluoromethyl)benzyl or 2-cyano Benzyl.

此方法較佳的係用於該等化合物，其中X為氯或溴原子，R1為苯基羰基甲基、苯甲基、萘基甲基、吡啶基甲基、嘧啶基甲基、喹啉基甲基、異喹啉基甲基、喹唑啉基甲基、喹啉基-甲基或萘啶基甲基，其中芳香或雜芳香基團在各情況下係經Ra單或雙取代，而其取代基可為相同或不同，及Ra為氫、氟或氯原子或氰基、甲基、乙基、甲氧基或乙氧基，R2為甲基、乙基、丙基、異丙基、環丙基或苯基及R3為2-丁烯-1-基、3-甲基-2-丁烯-1-基、2-丁炔-1-基、2-氟苯甲基、2-氯苯甲基、2-溴苯甲基、2-碘苯甲基、2-甲基苯甲基、2-(三氟甲基)苯甲基或2-氰基苯甲基。 This method is preferably used in the compounds wherein X is a chlorine or bromine atom and R 1 is phenylcarbonylmethyl, benzyl, naphthylmethyl, pyridylmethyl, pyrimidinylmethyl, quinoline Methyl, isoquinolinylmethyl, quinazolinylmethyl, quin a phenyl-methyl or naphthyridinylmethyl group, wherein the aromatic or heteroaromatic group is in each case mono- or disubstituted by R a , and the substituents may be the same or different, and R a is hydrogen, fluoro or Chlorine or cyano, methyl, ethyl, methoxy or ethoxy, R 2 is methyl, ethyl, propyl, isopropyl, cyclopropyl or phenyl and R 3 is 2-butene -1-yl, 3-methyl-2-buten-1-yl, 2-butyn-1-yl, 2-fluorobenzyl, 2-chlorobenzyl, 2-bromobenzyl, 2 -iodobenzyl, 2-methylbenzyl, 2-(trifluoromethyl)benzyl or 2-cyanobenzyl.

此方法更佳的係用於該等化合物，其中X為氯或溴原子 More preferred for use in such compounds, wherein X is a chlorine or bromine atom

R1為氰基苯甲基、(氰基吡啶基)甲基、喹啉基甲基、(甲基喹啉基)甲基、異喹啉基甲基、(甲基異喹啉基)甲基、喹唑啉基甲基、(甲基喹唑啉基)甲基、喹啉甲基、(甲基喹啉基)甲基、(二甲基喹啉基)甲基或萘啶基甲基，R2為甲基、環丙基或苯基及R3為2-丁烯-1-基、3-甲基-2-丁烯-1-基、2-丁炔-1-基、2-氯苯甲基、2-溴苯甲基或2-氰基苯甲基，但特別是對化合物1-[(4-甲基喹唑啉-2-基)甲基]-3-甲基-7-(2-丁炔-1-基)-8-(3-(R)-胺基六氫吡啶-1-基)-黄嘌呤、1-[(3-甲基異喹啉-1-基)甲基]-3-甲基-7-(2-丁炔-1-基)-8-((R)-3-胺基六氫吡啶-1-基)-黄嘌呤及1-[(3-氰基六氫吡啶-2-基)甲基]-3-甲基-7-(2-丁炔-1-基)-8-(3-(R)-胺基六氫吡啶-1-基)-黄嘌呤，其中X為溴。 R 1 is cyanobenzyl, (cyanopyridyl)methyl, quinolinylmethyl, (methylquinolinyl)methyl, isoquinolinylmethyl, (methylisoquinolinyl) A , quinazolinylmethyl, (methylquinazolinyl)methyl, quinine Phenylmethyl, (methyl quinine Phenyl)methyl, (dimethylquine Phenyl)methyl or naphthyridinylmethyl, R 2 is methyl, cyclopropyl or phenyl and R 3 is 2-buten-1-yl, 3-methyl-2-buten-1-yl , 2-butyn-1-yl, 2-chlorobenzyl, 2-bromobenzyl or 2-cyanobenzyl, but especially for the compound 1-[(4-methylquinazoline-2) -yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-(3-(R)-aminohexahydropyridin-1-yl)-xanthine, 1- [(3-Methylisoquinolin-1-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-((R)-3-aminohexahydropyridine -1-yl)-xanthine and 1-[(3-cyanohexahydropyridin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-( 3-(R)-Aminohexahydropyridin-1-yl)-xanthine, wherein X is bromine.

在各情況下較佳的係使用(R)-3-(酞醯亞胺基)六氫吡啶作為試劑。式(III)化合物之製備已描述於上述引用之文獻中，且可以本身已知之方法來進行。 In each case, (R)-3-(indenylamino)hexahydropyridine is preferably used as a reagent. The preparation of the compounds of formula (III) has been described in the above cited documents and can be carried out by methods known per se.

本發明進一步係提供製備光學活性3-(酞醯亞胺基)六氫吡啶之方法。在此方法中，先將3-胺基吡啶以本身已知之方法氫化。然後將由此得到之外消旋3-胺基六氫吡啶藉由酞酸酐轉變為對應的酞醯亞胺。該(R)對掌異構物可選擇性的從外消旋、粗酞醯亞胺(IV)溶液中藉由D-酒石酸沉澱出。毋須先將原來存在母液中之過量的D-酒石酸移除，以 簡單方法藉由添加L-酒石酸亦可能由鹽類沉澱之母液中得到(IV)之(S)對掌異構物。 The invention further provides a process for the preparation of optically active 3-(indenido)hexahydropyridine. In this method, 3-aminopyridine is first hydrogenated in a manner known per se. The racemic 3-aminohexahydropyridine thus obtained is then converted to the corresponding quinone imine by phthalic anhydride. The (R) palmar isomer can be selectively precipitated from the racemic, crude imine (IV) solution by D-tartaric acid. It is not necessary to remove excess D-tartaric acid from the original mother liquor first, A simple method is to obtain (S) palmar isomers of (IV) from the mother liquor of salt precipitation by adding L-tartaric acid.

此極度簡單的式(IV)化合物進行對掌異構物分離，令熟習本項技術者非常驚訝。由氫化反應得來之外消旋鹼不必預先純化來達到此目的。該等處理工作甚至在工業級製造仍無任何問題。 This extremely simple compound of formula (IV) is used to separate the palmomeromers, which is very surprising to those skilled in the art. The racemic base obtained from the hydrogenation reaction does not have to be previously purified to achieve this. There is still no problem with such processing work even at industrial grade manufacturing.

此外，3-胺基六氫吡啶與酞酸酐之格外完全的反應本身亦令人驚訝，因為根據文獻(例如美國專利4,005,208，特別是實例27)，除了所欲的產物外，混合物中預期會含有環氮經醯化之衍生物。 Furthermore, the exceptionally complete reaction of 3-aminopiperidine with phthalic anhydride is also surprising in itself, as it is expected to contain, in addition to the desired product, according to the literature (e.g., U.S. Patent 4,005,208, especially Example 27). A derivative of a ring nitrogen that has been deuterated.

下列實例將更詳細的說明本發明： The following examples will illustrate the invention in more detail:

實例1 Example 1 3-(酞醯亞胺基)六氫吡啶對掌異構物之D-酒石酸鹽3-(indenine)hexahydropyridine to palmo-isomer D-tartrate a.氫化作用：a. Hydrogenation:

將10.00 kg(106.25 mol)的3-胺基吡啶、500 g技術級的活性碳及65公升醋酸先裝入氫化反應器中。加入50 g的Nishimura催化劑(市售的銠/鉑晃何催化劑)於2.5公升的醋酸中形成漿液及沖入2.5公升的醋酸。於50℃及100 bar的氫氣壓下進行氫化，直到氫氣的吸收停止，及隨後於50℃進行後氫化反應30分鐘。將催化劑及活性碳濾出並以10公升的醋酸沖洗。毋須純化將產物溶液進行進一步的反應。 10.00 kg (106.25 mol) of 3-aminopyridine, 500 g of technical grade activated carbon and 65 liters of acetic acid were charged to the hydrogenation reactor. 50 g of Nishimura catalyst (commercially available rhodium/platinum catalyst) was added to form a slurry in 2.5 liters of acetic acid and flushed into 2.5 liters of acetic acid. Hydrogenation was carried out at 50 ° C under a hydrogen pressure of 100 bar until the absorption of hydrogen was stopped, and then hydrogenation was carried out at 50 ° C for 30 minutes. The catalyst and activated carbon were filtered off and rinsed with 10 liters of acetic acid. The product solution is subjected to further reaction without purification.

反應亦可在較不嚴謹的壓力下進行。 The reaction can also be carried out under less stringent pressure.

b.醯化作用b. Deuteration

先將15.74 kg(106.25 mol)的酞酸酐裝入反應器中，並與由氫化反應得來之濾液混合。將其沖入7.5公升的醋酸並隨後將反應混合物加熱回流，在此期間一小時內，約有30%所用的醋酸蒸餾出。將反應溶液冷卻至90℃。毋須純化將產物溶液進行進一步的反應。 First, 15.74 kg (106.25 mol) of phthalic anhydride was charged into the reactor and mixed with the filtrate obtained by the hydrogenation reaction. This was flushed into 7.5 liters of acetic acid and the reaction mixture was then heated to reflux, during which time about 30% of the acetic acid used was distilled off. The reaction solution was cooled to 90 °C. The product solution is subjected to further reaction without purification.

c.光學解析c. Optical analysis

將加熱至50℃、11.16 kg D(-)-酒石酸(74.38 mol)之50公升的無水乙醇溶液於90℃計量加入醯化反應溶液。將其沖入10公升的無水乙醇並於90℃攪拌30分鐘，在此期間有產物結晶出。冷卻至5℃後，將產物離心及以無水乙醇沖洗。毋須純化將產物溶液進行進一步的反應。 A 50 liter absolute ethanol solution heated to 50 ° C, 11.16 kg D(-)-tartaric acid (74.38 mol) was metered into the oximation reaction solution at 90 °C. This was poured into 10 liters of absolute ethanol and stirred at 90 ° C for 30 minutes, during which time the product crystallized. After cooling to 5 ° C, the product was centrifuged and rinsed with absolute ethanol. The product solution is subjected to further reaction without purification.

d.再結晶作用d. Recrystallization

將濕的粗產物置於50公升丙酮及90公升水之混合物中加熱回流直到溶液形成。隨後，溶液冷卻至5℃，在此期間有產物結晶出。將懸浮液於5℃攪拌30分鐘，並將產物離心，最後以20公升丙酮及10公升水之混合物沖洗。將混合物置於45℃惰性化乾燥箱中乾燥。 The wet crude product was placed in a mixture of 50 liters of acetone and 90 liters of water and heated to reflux until the solution formed. Subsequently, the solution was cooled to 5 ° C during which time the product crystallized out. The suspension was stirred at 5 ° C for 30 minutes, and the product was centrifuged and finally rinsed with a mixture of 20 liters of acetone and 10 liters of water. The mixture was dried in an inerting oven at 45 °C.

產率：11.7-12.5 kg(29-31%之理論值) Yield: 11.7-12.5 kg (29-31% of theoretical value)

實例2Example 2 合成1-[(4-甲基喹唑啉-2-基)甲基]-3-甲基-7-(2-丁炔-1-基)-8-(3-(R)-胺基六氫吡啶-1-基)-黄嘌呤Synthesis of 1-[(4-methylquinazolin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-(3-(R)-amino group Hexahydropyridin-1-yl)-anthraquinone a. 2-氯甲基-4-甲基喹唑啉a. 2-Chloromethyl-4-methylquinazoline

先裝入10.00 kg(73.98 mol)的2-胺基苯乙酮及加入24.5公升的1,4-二烷。將溶液冷卻至10℃，與16.72 kg(458.68 mol)的氯化氫覆蓋混合。將反應混合物回溫至22-25℃。於此溫度下另再覆蓋氯化氫。約至總覆蓋量的一半時，混合物冷卻至-10℃並持續覆蓋。隨後，將形成的懸浮液放置於-10℃下至隔夜。於-10℃，一小時內加入6.70 kg(88.78 mol)氯乙腈之2.5公升1,4-二烷溶液。於物料容器中沖入2公升的1,4-二烷。之後，將反應器的內容物加熱至6℃並再攪拌約2小時。 First fill 10.00 kg (73.98 mol) of 2-aminoacetophenone and add 24.5 liters of 1,4-two alkyl. The solution was cooled to 10 ° C and mixed with 16.72 kg (458.68 mol) of hydrogen chloride. The reaction mixture was warmed to 22-25 °C. At this temperature, it is additionally covered with hydrogen chloride. At about half of the total coverage, the mixture was cooled to -10 ° C and covered continuously. Subsequently, the resulting suspension was placed at -10 ° C until overnight. Add 2.5 liters of 1,4-two of 6.70 kg (88.78 mol) of chloroacetonitrile at -10 ° C over one hour. Alkane solution. 2 liters of 1,4-two into the material container alkyl. Thereafter, the contents of the reactor were heated to 6 ° C and stirred for a further 2 hours.

先於另一反應器中裝入122公升水及62.04 kg(775.31 mol)氫氧化鈉溶液(50%)之混合物並冷卻至6℃。分次加入第一反應器之反應混合物。內部的溫度不超過11℃。隨後，首先於第一反應器沖入6公升1,4-二烷，然後沖入6公升的水。將生成的懸浮液於5℃另再攪拌30分鐘。將產物離心，以41公升的水沖洗並於35℃惰性化乾燥箱中乾燥。. A mixture of 122 liters of water and 62.04 kg (775.31 mol) of sodium hydroxide solution (50%) was charged to another reactor and cooled to 6 °C. The reaction mixture of the first reactor was added in portions. The internal temperature does not exceed 11 °C. Subsequently, first, 6 liters of 1,4-two are flushed into the first reactor. The alkane is then flushed into 6 liters of water. The resulting suspension was stirred for an additional 30 minutes at 5 °C. The product was centrifuged, rinsed with 41 liters of water and dried in an inerting oven at 35 °C. .

產率：10.5-12.1 kg(74-85%之理論值) Yield: 10.5-12.1 kg (74-85% of theoretical value)

b. 1-[(4-甲基喹唑啉-2-基)甲基]-3-甲基-7-(2-丁炔-1-基)-8-溴黄嘌呤b. 1-[(4-Methylquinazolin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-bromoxanthine

將10.00 kg(33.66 mol)3-甲基-7-(2-丁炔-1-基)-8-溴黄嘌呤、7.13 kg(37.02 mol)2-氯甲基-4-甲基喹唑啉、3.92 kg (37.02 mol)無水碳酸鈉及30公升N-甲基-2-吡咯酮先裝入反應中。將反應器內容物加熱至140℃並於140℃攪拌2小時。反應結束後，將反應混合物冷卻至80℃並以60公升的96%乙醇稀釋，隨後於70℃以55公升的水稀釋。於60℃，計量加入4.04 kg(67.32 mol)醋酸並沖入5公升的水。將生成的懸浮液於60℃攪拌30分鐘，然後冷卻至23℃並另再攪拌30分鐘。隨後將產物離心並先以20公升96%乙醇及20公升水之混合物沖洗，然後以40公升96%乙醇及40公升水之混合物沖洗。於45℃惰性化乾燥箱中乾燥。 10.00 kg (33.66 mol) 3-methyl-7-(2-butyn-1-yl)-8-bromoxanthine, 7.13 kg (37.02 mol) 2-chloromethyl-4-methylquinazoline , 3.92 kg (37.02 mol) anhydrous sodium carbonate and 30 liters of N-methyl-2-pyrrolidone were first charged into the reaction. The reactor contents were heated to 140 ° C and stirred at 140 ° C for 2 hours. After the reaction was completed, the reaction mixture was cooled to 80 ° C and diluted with 60 liters of 96% ethanol, followed by dilution at 55 ° C with 55 liters of water. At 60 ° C, 4.04 kg (67.32 mol) of acetic acid was metered in and flushed into 5 liters of water. The resulting suspension was stirred at 60 ° C for 30 minutes, then cooled to 23 ° C and stirred for a further 30 minutes. The product was then centrifuged and rinsed first with a mixture of 20 liters of 96% ethanol and 20 liters of water, then rinsed with a mixture of 40 liters of 96% ethanol and 40 liters of water. Dry in an inerting oven at 45 °C.

產率：11.6-12.6 kg(76-83%之理論值) Yield: 11.6-12.6 kg (76-83% of theoretical value)

c. 1-[(4-甲基喹唑啉-2-基)甲基]-3-甲基-7-(2-丁炔-1-基)-8-(3-(R)-酞醯亞胺基六氫吡啶-1-基)-黄嘌呤c. 1-[(4-Methylquinazolin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-(3-(R)-indole Yttrium iminopyridin-1-yl)-xanthine

將10.00 kg(22.06 mol)1-[(4-甲基喹唑啉-2-基)甲基]-3-甲基-7-(2-丁炔-1-基)-8-溴黄嘌呤、12.59 kg(33.09 mol)3-(酞醯亞胺基)六氫吡啶D-酒石酸鹽及17.5公升的N-甲基-2-吡咯酮先裝入反應器中。將反應器內容物加熱至140℃。達到此溫度後，於20分鐘內計量加入11.41 kg(88.24 mol)的二異丙基乙基胺。於原料容器中沖入2.5公升的N-甲基-2-吡咯酮及隨後將反應混合物於140℃攪拌2小時。反應結 束後，將反應混合物冷卻至60℃並以80公升的甲醇稀釋。將生成的懸浮液於50℃攪拌30分鐘，然後冷卻至23℃並另再攪拌30分鐘。隨後將產物離心並各以20公升的甲醇沖洗3次。於45℃惰性化乾燥箱中乾燥。 10.00 kg (22.06 mol) of 1-[(4-methylquinazolin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-bromoxanthine 12.59 kg (33.09 mol) of 3-(indenine)hexahydropyridine D-tartrate and 17.5 liters of N-methyl-2-pyrrolidone were first charged into the reactor. The reactor contents were heated to 140 °C. After reaching this temperature, 11.41 kg (88.24 mol) of diisopropylethylamine was metered in over 20 minutes. 2.5 liters of N-methyl-2-pyrrolidone was flushed into the raw material container and the reaction mixture was then stirred at 140 ° C for 2 hours. Reaction junction After the bundle, the reaction mixture was cooled to 60 ° C and diluted with 80 liters of methanol. The resulting suspension was stirred at 50 ° C for 30 minutes, then cooled to 23 ° C and stirred for a further 30 minutes. The product was then centrifuged and each rinsed 3 times with 20 liters of methanol. Dry in an inerting oven at 45 °C.

產率：12.0-12.5 kg(90-94%之理論值) Yield: 12.0-12.5 kg (90-94% of theoretical value)

d. 1-[(4-甲基喹唑啉-2-基)甲基]-3-甲基-7-(2-丁炔-1-基)-8-(3-(R)-胺基六氫吡啶-1-基)-黄嘌呤d. 1-[(4-Methylquinazolin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-(3-(R)-amine Hexahydropyridin-1-yl)-xanthine

將1800 kg(3 mol)的1-[(4-甲基喹唑啉-2-基)甲基]-3-甲基-7-(2-丁炔-1-基)-8-(3-(R)-酞醯亞胺基六氫吡啶-1-基)-黄嘌呤於18公升的甲苯中加熱至80-85℃。隨後，於75-80℃將1.815公升(30 mol)之乙醇胺加到懸浮液中。將混合物於80-85℃攪拌2小時使反應完全，在此期間有固體溶到溶液中。隨後進行相分離。以溫甲苯沖洗乙醇胺層二次(每次4公升)。將組合的甲苯層每次各以8公升的水於75-80℃沖洗二次。由甲苯層，將22公升的甲苯於減壓下蒸餾出。於40-50℃計量4公升的第三-丁基甲基醚加至生成的懸浮液中並隨後冷卻至0-5℃。過濾將產物分離出，以第三丁基甲基醚沖洗並抽氣乾燥。之後以5倍量之無水乙醇將濕的粗物質加熱回流並將該熱溶液經由活性碳過濾淨化。將濾液冷卻至20℃後，結晶作用開始，將其以第三丁基甲基醚稀 釋成二倍體積。將懸浮液冷卻至2℃，另再攪拌2小時，抽氣過濾並於45℃乾燥箱中乾燥。 1800 kg (3 mol) of 1-[(4-methylquinazolin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-(3 -( R )-indolylpyridin-1-yl)-xanthine was heated to 80-85 ° C in 18 liters of toluene. Subsequently, 1.815 liters (30 mol) of ethanolamine was added to the suspension at 75-80 °C. The mixture was stirred at 80-85 ° C for 2 hours to complete the reaction, during which time a solid dissolved in the solution. The phase separation is then carried out. The ethanolamine layer was washed twice with warm toluene (4 liters each time). The combined toluene layers were rinsed twice with 8 liters of water each at 75-80 °C. From the toluene layer, 22 liters of toluene was distilled off under reduced pressure. 4 liters of third-butyl methyl ether was added to the resulting suspension at 40-50 ° C and then cooled to 0-5 ° C. The product was isolated by filtration, washed with tributylmethyl ether and dried with suction. The wet crude material was then heated to reflux with 5 times the amount of absolute ethanol and the hot solution was purified by filtration through activated carbon. After cooling the filtrate to 20 ° C, crystallization started and it was diluted to a double volume with a third butyl methyl ether. The suspension was cooled to 2 ° C, stirred for an additional 2 hours, suction filtered and dried in a 45 ° C dry box.

產率：1174 g(83.2%之理論值) Yield: 1174 g (83.2% of theory)

步驟d之另一種方法：Another method of step d:

將1400 g(2.32 mol)的1-[(4-甲基喹唑啉-2-基)甲基]-3-甲基-7-(2-丁炔-1-基)-8-(3-(R)-酞醯亞胺基六氫吡啶-1-基)-黄嘌呤先置入4.9 l的四氫呋喃中，隨後加熱至55-65℃。 1400 g (2.32 mol) of 1-[(4-methylquinazolin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-(3 -( R )-indolylpyridin-1-yl)-xanthine was first placed in 4.9 l of tetrahydrofuran, followed by heating to 55-65 °C.

之後，將350 ml的水及1433 g(2.32 mol)的乙醇胺加到懸浮液中。將混合物於60-63℃再攪拌3小時使反應完全。之後，加入619 ml 45%的氫氧化鈉溶液及3.85 l的水，並將混合物於55-65℃攪拌30分鐘。然後於反應混合物中加入5.6 l的甲苯，將混合物攪拌15分鐘，之後進行相分離。以2.8 l的水於55-65℃沖洗有機層，之後移出。從有機層，減壓下蒸餾出4.2 l。之後，於65-75℃加入1.4 l的甲基環己烷，在此期間產物結晶出。將懸浮液於15-25℃攪拌8-16小時，然後冷卻至0-5℃。將產物過濾分離，以4.2 l的甲基環己烷沖洗，抽氣乾燥並於35℃減壓乾燥。隨後將乾燥的粗物質(991 g)以5倍量之甲醇加熱回流，加入活性碳及過濾混合物。將甲醇蒸餾出使濾液體積降至1.5 l。將濾液冷卻至45-55℃，以第三丁基甲基醚稀釋成四倍體積。懸浮液冷卻至0-5℃，攪拌2小時，抽氣過濾、以第三丁基甲基醚沖洗並於35℃真空乾燥箱中乾燥。 Thereafter, 350 ml of water and 1433 g (2.32 mol) of ethanolamine were added to the suspension. The mixture was stirred at 60-63 ° C for an additional 3 hours to complete the reaction. Thereafter, 619 ml of a 45% sodium hydroxide solution and 3.85 l of water were added, and the mixture was stirred at 55 to 65 ° C for 30 minutes. Then, 5.6 l of toluene was added to the reaction mixture, and the mixture was stirred for 15 minutes, followed by phase separation. The organic layer was rinsed with 2.8 l of water at 55-65 ° C and then removed. From the organic layer, 4.2 l was distilled off under reduced pressure. Thereafter, 1.4 l of methylcyclohexane was added at 65-75 ° C, during which time the product crystallized. The suspension was stirred at 15-25 ° C for 8-16 hours and then cooled to 0-5 °C. The product was isolated by filtration, washed with EtOAc (EtOAc), EtOAc (EtOAc). The dried crude material (991 g) was then heated to reflux with 5 times methanol, activated carbon and filtered mixture. The methanol was distilled off to reduce the filtrate volume to 1.5 l. The filtrate was cooled to 45-55 ° C and diluted to four volumes with tributyl methyl ether. The suspension was cooled to 0-5 ° C, stirred for 2 hours, filtered off with suction, rinsed with tri-butyl methyl ether and dried in a vacuum oven at 35 ° C.

產率：899 g(81.9%理論值) Yield: 899 g (81.9% of theory)

實例3 Example 3 1-[(3-氰基吡啶-2-基)甲基]-3-甲基-7-(2-丁炔-1-基)-8-(3-(R)-胺基六氫吡啶-1-基)-黄嘌呤1-[(3-cyanopyridin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-(3-(R)-aminohexahydropyridine -1-base)-黄嘌呤 a. 3-氰基-2-(氯甲基)-吡啶a. 3-cyano-2-(chloromethyl)-pyridine

將165.5 g(0.98 mol)的2-羥基甲基-3-吡啶甲醯胺與270 ml的***共同加熱至90-100℃歷經1小時。將反應混合物冷卻至室溫及隨後於50-60℃逐滴加入約800 ml的水。待***水解後，以氫氧化鈉溶液冷卻中和，在此期間有產物沉澱出。將其過濾，以300 ml的水沖洗及隨後於35-40℃下乾燥。 165.5 g (0.98 mol) of 2-hydroxymethyl-3-pyridinecarboxamide was heated together with 270 ml of phosphorus oxychloride to 90-100 ° C for 1 hour. The reaction mixture was cooled to room temperature and then about 800 ml of water was added dropwise at 50-60 °C. After the phosphorus oxychloride was hydrolyzed, it was cooled and neutralized with a sodium hydroxide solution, during which time a product precipitated. It was filtered, rinsed with 300 ml of water and then dried at 35-40 °C.

產率：122.6 g(82%之理論值) Yield: 122.6 g (82% of theory)

步驟a之變化：3-氰基-2-(氯甲基)吡啶Step a change: 3-cyano-2-(chloromethyl)pyridine

將20.0 g(131.45 mmol)的2-羥基甲基-3-吡啶甲醯胺懸浮於110 ml的乙腈中並加熱至78℃。逾15分鐘內，量取60.65 g(395.52 mmol)的***至混合物中並將混合物加熱至81℃歷經2小時。於22℃冷卻後，將反應混合物置於200 ml的水中於40℃下攪拌。加入100 ml的甲苯後，以氫氧化鈉溶液冷卻中和。進行相分離後，以100 ml的水沖洗有機層。移出有機層並減壓蒸發溶劑得到起初生成的油狀物，將其靜置使其結晶。 20.0 g (131.45 mmol) of 2-hydroxymethyl-3-pyridinecarboxamide was suspended in 110 ml of acetonitrile and heated to 78 °C. 60.65 g (395.52 mmol) of phosphorus oxychloride was weighed into the mixture over 15 minutes and the mixture was heated to 81 ° C for 2 hours. After cooling at 22 ° C, the reaction mixture was placed in 200 ml of water and stirred at 40 ° C. After adding 100 ml of toluene, it was cooled and neutralized with a sodium hydroxide solution. After phase separation, the organic layer was rinsed with 100 ml of water. The organic layer was removed and the solvent was evaporated under reduced pressure to give an oil which was initially formed, which was allowed to stand to crystallize.

產率：16.66 g(83%之理論值) Yield: 16.66 g (83% of theory)

b. 1-[(3-氰基吡啶-2-基)甲基]-3-甲基-7-(2-丁炔-1-基)-8-溴黄嘌呤b. 1-[(3-Cyanopyridin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-bromoxanthine

將202 g(0.68 mol)的3-甲基-7-(2-丁炔-1-基)-8-溴黄嘌呤、188.5 g(1.36 mol)的無水碳酸鉀及1.68公升的N-甲基-2-吡咯酮先裝入反應器中並加熱至70℃。隨後，逐滴加入119 g(0.75 mol)的2-氯甲基-3-氰基吡啶之240 ml的N-甲基-2-吡咯酮(NMP)溶液。將反應內容物於70℃下攪拌19小時。待反應結束後，將2.8公升的水加到反應混合物中並冷卻至25℃。將產物過濾出，以2公升的水沖洗並於70℃惰性化乾燥箱中乾燥。 202 g (0.68 mol) of 3-methyl-7-(2-butyn-1-yl)-8-bromoxanthine, 188.5 g (1.36 mol) of anhydrous potassium carbonate and 1.68 liters of N-methyl The -2-pyrrolidone was first charged into the reactor and heated to 70 °C. Subsequently, a solution of 119 g (0.75 mol) of 2-chloromethyl-3-cyanopyridine in 240 ml of N-methyl-2-pyrrolidone (NMP) was added dropwise. The reaction contents were stirred at 70 ° C for 19 hours. After the reaction was completed, 2.8 liters of water was added to the reaction mixture and cooled to 25 °C. The product was filtered off, rinsed with 2 liters of water and dried in a 70 ° C inert oven.

產率：257.5 g(91%之理論值) Yield: 257.5 g (91% of theory)

c. 1-[(3-氰基吡啶-2-基)甲基]-3-甲基-7-(2-丁炔-1-基)-8-(3-(R)-酞醯亞胺基六氫吡啶-1-基)-黄嘌呤c. 1-[(3-Cyanopyridin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-(3-(R)-酞醯亚Amino hexahydropyridin-1-yl)-xanthine

將230 g(0.557 mol)的1-[(3-氰基吡啶-2-基)甲基]-3-甲基-7-(2-丁炔-1-基)-8-溴黄嘌呤、318 g(0.835 mol)的3-(酞醯亞胺基)六氫吡啶D-酒石酸鹽及1.15公升的N-甲基-2-吡咯酮先裝入反應器中。將反應器加熱至140℃。待達到此溫度後，逾20分鐘內計量加入478 ml(2.78 mol)的二異丙基乙基胺，隨後並將反應混合物140℃攪拌2小時。之後， 將反應混合物冷卻至75℃並以720 ml的甲醇稀釋，之後，於68-60℃加入2.7公升水並將混合物冷卻至25℃。將產物過濾出並以2公升的水沖洗。於70℃惰性化乾燥箱中進行乾燥。 230 g (0.557 mol) of 1-[(3-cyanopyridin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-bromoxanthine, 318 g (0.835 mol) of 3-(indenine)hexahydropyridine D-tartrate and 1.15 liters of N-methyl-2-pyrrolidone were first charged into the reactor. The reactor was heated to 140 °C. After reaching this temperature, 478 ml (2.78 mol) of diisopropylethylamine were metered in over 20 minutes, and the reaction mixture was stirred at 140 ° C for 2 hours. after that, The reaction mixture was cooled to 75 ° C and diluted with 720 ml of methanol, after which 2.7 liters of water was added at 68-60 ° C and the mixture was cooled to 25 ° C. The product was filtered off and rinsed with 2 liters of water. Drying was carried out in an inert oven at 70 °C.

之後將得到的粗產物置於1公升的甲醇中煮沸，熱過濾，以200 ml的甲醇沖洗，隨後於70℃惰性化條件下乾燥。 The obtained crude product was then placed in 1 liter of methanol, boiled, filtered hot, rinsed with 200 ml of methanol, and then dried under inert conditions at 70 °C.

產率：275 g(88%之理論值) Yield: 275 g (88% of theory)

d. 1-[(3-氰基吡啶-2-基)甲基]-3-甲基-7-(2-丁炔-1-基)-8-(3-(R)-胺基六氫吡啶-1-基)-黄嘌呤d. 1-[(3-Cyanopyridin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-(3-(R)-amino 6 Hydropyridin-1-yl)-xanthine

將412.5 g(0.733 mol)的1-[(3-氰基吡啶-2-基)甲基]-3-甲基-7-(2-丁炔-1-基)-8-(3-(R)-酞醯亞胺基六氫吡啶-1-基)-黄嘌呤溶於4125 ml的甲苯中加熱至80℃。隨後於75-80℃將445 ml的乙醇胺(7.33 mol)加到懸浮液中。將混合物於80-85℃再攪拌2小時，使反應完全，在此期間有固體進入溶液中。之後，進行相分離。將乙醇胺層以溫甲苯萃取二次(每次1公升)。將組合的甲苯層於75-80℃以每次2公升的水沖洗二次。硫酸鈉乾燥甲苯層，過濾並隨後於減壓下蒸餾將體積降至約430 ml。之後於50-55℃計量加入1公升的第 三丁基甲醚，然後將混合物冷卻至0-5℃。將產物過濾分離，以第三丁基甲基醚沖洗並於60℃乾燥箱中乾燥。 412.5 g (0.733 mol) of 1-[(3-cyanopyridin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-(3-( R )-酞醯iminopyridin-1-yl)-xanthine was dissolved in 4125 ml of toluene and heated to 80 °C. Subsequently, 445 ml of ethanolamine (7.33 mol) was added to the suspension at 75-80 °C. The mixture was stirred at 80-85 ° C for an additional 2 hours to complete the reaction during which time solids entered the solution. After that, phase separation is performed. The ethanolamine layer was extracted twice with warm toluene (1 liter each time). The combined toluene layer was rinsed twice at 7-80 ° C with 2 liters of water each time. The toluene layer was dried over sodium sulfate, filtered and then distilled under reduced pressure to reduce the volume to about 430 ml. One liter of third butyl methyl ether was then metered in at 50-55 ° C and the mixture was cooled to 0-5 ° C. The product was isolated by filtration, washed with tributylmethyl ether and dried in a dry oven at 60 °C.

產率：273 g(86%之理論值) Yield: 273 g (86% of theory)

熔點：188±3℃ Melting point: 188±3°C

類似實例2及3，製備出1-[(3-甲基異喹啉-1-基)甲基]-3-甲基-7-(2-丁炔-1-基)-8-((R)-3-胺基六氫吡啶-1-基)-黄嘌呤。 Similar to Examples 2 and 3, 1-[(3-methylisoquinolin-1-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-(( R)-3-Aminohexahydropyridin-1-yl)-xanthine.

Claims (7)

一種下列通式之化合物或其對掌異構物或鹽類， 其中R1為苯基羰基甲基、苯甲基、萘基甲基、吡啶基甲基、嘧啶基甲基、喹啉基甲基、異喹啉基甲基、喹唑啉基甲基、喹啉基甲基、萘啶基甲基或啡啶基甲基，其中芳香或雜芳香基團係各自經Ra單或雙取代，而其取代基可為相同或不同，及Ra為氫、氟、氯或溴原子或氰基、甲基、三氟甲基、乙基、苯基、甲氧基、二氟甲氧基、三氟甲氧基或乙氧基，或二個Ra基，當與相鄰的碳原子鍵結時，亦可為-O-CH2-O-或-O-CH2-CH2-O-基，R2為甲基、乙基、丙基、異丙基、環丙基或苯基及R3為2-丁烯-1-基、3-甲基-2-丁烯-1-基、2-丁炔-1-基、2-氟苯甲基、2-氯苯甲基、2-溴苯甲基、2-碘苯甲基、2-甲基苯甲基、2-(三氟甲基)苯甲基或2-氰基苯甲基，該化合物係藉由下列合成步驟獲得：a)將通式(III)之化合物 其中X為離去基，其係選自鹵素或磺醯酯，及R1至R3各係如上述之定義，與3-(酞醯亞胺基)六氫吡啶或其對掌異構物反應，b)將得到的通式(II)化合物去保護 其中R1至R3各係如上述之定義，及c)視需要轉變為生理上可耐受之鹽類。 a compound of the formula: or a palmitic isomer or salt thereof, Wherein R 1 is phenylcarbonylmethyl, benzyl, naphthylmethyl, pyridylmethyl, pyrimidinylmethyl, quinolinylmethyl, isoquinolinylmethyl, quinazolinylmethyl, quinolin a phenylmethyl group, a naphthyridylmethyl group or a phenazinylmethyl group, wherein the aromatic or heteroaromatic group is each mono- or disubstituted by R a , and the substituents may be the same or different, and R a is hydrogen, Fluorine, chlorine or bromine atom or cyano group, methyl, trifluoromethyl, ethyl, phenyl, methoxy, difluoromethoxy, trifluoromethoxy or ethoxy, or two R a groups When bonded to an adjacent carbon atom, it may also be -O-CH 2 -O- or -O-CH 2 -CH 2 -O- group, and R 2 is a methyl group, an ethyl group, a propyl group or a different group. Propyl, cyclopropyl or phenyl and R 3 are 2-buten-1-yl, 3-methyl-2-buten-1-yl, 2-butyn-1-yl, 2-fluorobenz Base, 2-chlorobenzyl, 2-bromobenzyl, 2-iodobenzyl, 2-methylbenzyl, 2-(trifluoromethyl)benzyl or 2-cyanobenzyl This compound is obtained by the following synthetic procedure: a) a compound of the formula (III) Wherein X is a leaving group selected from halogen or sulfonate, and each of R 1 to R 3 is as defined above, and 3-(indenido)hexahydropyridine or its palmomer isomer Reaction, b) deprotection of the obtained compound of the general formula (II) Wherein each of R 1 to R 3 is as defined above, and c) is converted to a physiologically tolerable salt as needed. 如請求項1之化合物，其中X為氯或溴原子，R1為苯基羰基甲基、苯甲基、萘基甲基、吡啶基甲基、嘧啶基甲基、喹啉基甲基、異喹啉基甲基、喹唑啉基甲基、喹啉基甲基或萘啶基甲基，其中芳香或雜芳香基團係各自經Ra單或雙取代，而其取代基可為相同或不同，及 Ra為氫、氟或氯原子或氰基、甲基、乙基、甲氧基或乙氧基，R2為甲基、乙基、丙基、異丙基、環丙基或苯基及R3為2-丁烯-1-基、3-甲基-2-丁烯-1-基、2-丁炔-1-基、2-氟苯甲基、2-氯苯甲基、2-溴苯甲基、2-碘苯甲基、2-甲基苯甲基、2-(三氟甲基)苯甲基或2-氰基苯甲基。 The compound of claim 1, wherein X is a chlorine or bromine atom, and R 1 is phenylcarbonylmethyl, benzyl, naphthylmethyl, pyridylmethyl, pyrimidinylmethyl, quinolinylmethyl, or different Quinoline methyl, quinazolinylmethyl, quin Orolinylmethyl or naphthyridylmethyl, wherein the aromatic or heteroaromatic groups are each mono- or disubstituted by R a , and the substituents may be the same or different, and R a is hydrogen, fluorine or chlorine or cyanide Base, methyl, ethyl, methoxy or ethoxy, R 2 is methyl, ethyl, propyl, isopropyl, cyclopropyl or phenyl and R 3 is 2-buten-1-yl , 3-methyl-2-buten-1-yl, 2-butyn-1-yl, 2-fluorobenzyl, 2-chlorobenzyl, 2-bromobenzyl, 2-iodophenyl Base, 2-methylbenzyl, 2-(trifluoromethyl)benzyl or 2-cyanobenzyl. 如請求項2之化合物，其中X為氯或溴原子R1為氰基苯甲基、(氰基吡啶基)甲基、喹啉基甲基、(甲基喹啉基)甲基、異喹啉基甲基、(甲基異喹啉基)甲基、喹唑啉基甲基、(甲基喹唑啉基)甲基、喹啉甲基、(甲基喹啉基)甲基、(二甲基喹啉基)甲基或萘啶基甲基，R2為甲基、環丙基或苯基及R3為2-丁烯-1-基、3-甲基-2-丁烯-1-基、2-丁炔-1-基、2-氯苯甲基、2-溴苯甲基或2-氰基苯甲基。 A compound according to claim 2, wherein X is a chlorine or a bromine atom, R 1 is cyanobenzyl, (cyanopyridyl)methyl, quinolinylmethyl, (methylquinolinyl)methyl, isoquinoline Polinylmethyl, (methylisoquinolinyl)methyl, quinazolinylmethyl, (methylquinazolinyl)methyl, quin Phenylmethyl, (methyl quinine Phenyl)methyl, (dimethylquine Phenyl)methyl or naphthyridinylmethyl, R 2 is methyl, cyclopropyl or phenyl and R 3 is 2-buten-1-yl, 3-methyl-2-buten-1-yl , 2-butyn-1-yl, 2-chlorobenzyl, 2-bromobenzyl or 2-cyanobenzyl. 如請求項3之化合物，其中X為溴原子，R1為(4-甲基喹唑啉-2-基)甲基、(3-甲基異喹啉-1-基)甲基或(3-氰基吡啶-2-基)甲基，R2為甲基及R3為2-丁炔-1-基。 The compound of claim 3, wherein X is a bromine atom, R 1 is (4-methylquinazolin-2-yl)methyl, (3-methylisoquinolin-1-yl)methyl or (3) -Cyanopyridin-2-yl)methyl, R 2 is methyl and R 3 is 2-butyn-1-yl. 如請求項1至4中任一項之化合物，其中(R)-3-(酞醯亞胺 基)六氫吡啶係用於步驟a)中作為反應物。 The compound of any one of claims 1 to 4, wherein (R)-3-(indenine) The hexahydropyridine is used as a reactant in step a). 一種醫藥品，其係包含如請求項1至5中任一項之化合物及視需要一或多種惰性載劑及/或稀釋劑。 A pharmaceutical product comprising a compound according to any one of claims 1 to 5 and optionally one or more inert carriers and/or diluents. 一種如請求項1至5中任一項之化合物之用途，其係用於製造適合供治療第I型及第II型糖尿病、前糖尿病癥兆或低葡萄糖耐受、關節炎、肥胖症、同種異體移植及降鈣素引起的骨質疏鬆症之醫藥品。 Use of a compound according to any one of claims 1 to 5 for the manufacture of Type I and Type II diabetes, pre-diabetes or low glucose tolerance, arthritis, obesity, homologous Allogeneic transplantation and osteoporosis caused by calcitonin.
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